Withania somnifera Overview - May 2021

By Michael Thomsen, MSc, ND

Michael Thomsen is herbalist and naturopath. Originally from Denmark, he completed studies in Naturopathy and Herbal Medicine in Sydney, graduating in 1986. Michael specialises in integrative oncology supporting patients with lifestyle and dietary advice, nutritional and herbal medicines and hyperthermia via allied clinics. His company, Eusano Healthcare, has pioneered whole body and local hyperthermia in Australia, importing and distributing ARTG listed medical infrared and hyperthermia devices made in Germany. He has a Master of Science, Graduate School of Integrative Medicine, Swinburne University and is currently a PhD scholar at Sydney University Medical School. Michael is researching chemotherapy-induced mucositis, intestinal dysbiosis and the possible role of probiotics as adjunct medicines in cancer care. Michael has extensive industry experience as past technical manager of leading herbal medicine companies in Australia. 

He is the author of the popular Phytotherapy Desk Reference now in its fifth edition having sold 10,000 copies worldwide. www.phytotherapydeskreference.com

Background

Introduced to Australian practitioners of Western Herbal Medicine in the mid-90s, Withania rapidly became a much-loved herb and is now one of the top selling herb in Australia and even in the UK. Ashwagandha (Withania  somnifera) is used in Ayurvedic medicine to promote youthful vigour, enhance muscle strength and endurance, and improve overall health. Ashwagandha’s popularity is no doubt related to its use as a relaxing or non-stimulating adaptogen and tonic and because it is considered safe for use in children.

Withania Review

Tandon et al. (2020) published a review of withania, which included studies published up to early 2019 [1]. No meta-analysis was performed presumably due to a paucity of studies for each condition.

Methods

A systematic search both for indexed and non-indexed literature was made for W. somnifera using various search engines and databases and the details of research articles pertaining to all clinical trials/human studies, animal studies addressing safety issues of CNS, CVS, general toxicity, mutagenicity, genotoxicity, re-productive safety and herb-drug interactions were reviewed and compiled comprehensively from full texts.

Results

A total of 69 (39 pre-clinical and 30 clinical) studies documenting efficacy and safety aspects were identified and the desired information of these studies is comprehensively presented in this review.

Retrieved thirty (30) human studies demonstrated reasonable efficacy of root preparations in:

1. subclinical hypothyroidism (1)
2. schizophrenia (3)
3. chronic stress (2)
4. insomnia (2)
5. anxiety (1)
6. memory and cognitive improvement (2)
7. obsessive-compulsive disorder (1)
8. rheumatoid arthritis (2)
9. type-2 diabetes (2)
10. male infertility (6)
11. fertility promotion activity in females (1)
12. adaptogenic (3)
13. growth promoter in children (3)
14. chemotherapy adjuvant (1)

Reasonable safety of root preparations of Aswagandha has been established by these retrieved 30 human trials.

• No serious adverse events or any changes in haematological, biochemical or vital parameters were re-ported in these human studies.
• Only mild and mainly transient type adverse events of somnolence, epigastric pain/discomfort and loose stools were reported as most common (> 5%); and giddiness, drowsiness, hallucinogenic, vertigo, nasal congestion (rhinitis), cough, cold, decreased appetite, nausea, constipation, dry mouth, hyperactivity, nocturnal cramps, blurring of vision, hyperacidity, skin rash and weight gain were reported as less common adverse events.
• Pre-clinical chronic toxicity studies conducted up to 8 months also found root extracts to be safe.
• No mutagenicity or genotoxicity was reported for the root; only mild CNS depression and increase in thyroxine (T4) levels were reported with root by some studies. Further, there was no in-vitro and in-vivo inhibition seen forCYP3A4 and CYP2D6, the two major hepatic drug metabolizing enzymes.

Conclusion

Clinical Research

A recent 16-week, randomized, double-blind, placebo-controlled, crossover study (n=50) found that a Withania extract known as Shoden beads for 8 weeks was associated with an 18% greater increase in DHEA-S (p = 0.005) and 14.7% greater increase in testosterone ( p = 0.010) compared to the placebo in overweight men (40-70 years) with symptoms of mild fatigue. The study found no significant improvement in cortisol, oestradiol, fatigue, vigour or sexual well-being.[2]

Shoden beads is manufactured by Arjuna Natural in Kerala, India from the roots and leaves of Withania. Shoden beads contain an extract standardised to eight withanolide glycosides with a reported high level of withanoside X (number 10). The total withanolide concentration 35% with each bead containing extract equivalent 10.5 mg withanolides. The dose was two tablets twice daily thus providing a total of 21 mg withanolides daily. 

In another study by the same group, 240 mg daily of the Shoden beads was shown to reduce symptoms of anxiety as measured by the Hamilton Anxiety Rating Scale (HAM-A) in a 60 day RCT of adults with self-reported high stress levels.[3] Now that would be equivalent to 84 mg withanolides daily, a much greater dose than the previous study (four-fold higher). Interestingly, they also measured the response with another scale, the Stress Scale -21 (DASS-21), but the improvement was not statistically significant.

There are 28 clinical trials with Withania published on PubMed examining various conditions including osteoarthritis, hyperglycaemia, dyslipidaemia, sleep, anxiety, stress, degenerative disease, semen quality, infertility, immune modulation, ADHD in children, schizophrenia, cognitive dysfunction in bipolar disorder, memory and cognition, OCD, maintenance of body weight during stress, hypothyroidism, strength training and depression in schizophrenia. These are single, generally small studies and while some may have suffered bias and poor methodology, several used standardised extracts and seems of good quality. Together, the studies provide an indication for how you may use Withania in clinical practice. 

A few of the studies used a standardised extract. Two, as mentioned, used Shoden beads. Another study used the Sensoril product (Natreon). 

Sensoril is an aqueous extract standardised to contain 8% withanolides comprising of 2% withaferin A; and 32% oligosaccharides. The dose was 250 mg extract daily, which is equivalent to 20 mg withanolides. The study examined the effects of cognitive function in people with bipolar disorder.[4] A second study based on Sensoril examined the effects on stress in people with schizophrenia.[5]. A third study examined adaptation and recovery associated with strength training.[6]

KSM-66

Another study used 300 mg of a standardized (containing 5% withanolides) Ashwagandha root extract KSM-66 Ashwagandha from Indian company, Ixoreal Biomed. This is of course equivalent to 15 mg total withanolides. This RCT examined the anxiolytic effects of Withania.[7] KSM-66 is based on the root only (as it should be). Some of the other extracts are based on root and leaves. The primary use of leaves traditionally was for topical treatments on the skin for conditions like burns or carbuncles, not internal consumption. 

KSM-66 was recently found to normalise thyroid hormone levels in an RCT of people with subclinical hypothyroidism.[8] The authors suggest caution in the use of Withania in hyperthyroidism. This is speculative although there has been one published case report with a possibility of thyrotoxicosis induced by Withania.[9] The case report is in Dutch and I have not read it, but I know from the examination of many other such case reports that a causal connection is rarely reported. 

A second case report of potential thyrotoxicosis was recently published: A 62-year-old female, in otherwise good health, was diagnosed with thyrotoxicosis after self-medication with Withania somnifera (Ashwagandha). She began supplementing with Ashwagandha root extract for stress and anxiety relief. After about two months of consistent daily dosing at 1950 mg, she experienced worsened anxiety, hysteric behaviours, extreme physical fatigue, unintentional weight loss, lack of concentration, poor memory, and increased resting heart rate. A physical examination determined her thyroid was uniformly enlarged, with tenderness to palpation and odynophagia. Laboratory results revealed low thyroid-stimulating hormone and elevated thyroxine, confirming hyperthyroidism, and borderline anaemia evidenced by low haematocrit and red blood cell distribution width. After discontinuation of Ashwagandha, the patient’s symptoms resolved, weight normalized, and subsequent laboratory values displayed normal thyroid functioning.[10]

Withania somnifera products and standardised extracts

Much of the pharmacological activity has been attributed to the two main withanolides, withaferin A and withanolide D. Unfortunately, these are not specifically referenced by the branded extracts. This renders it difficult to be confident on the therapeutic reproducibility of these products*.

Branded extracts

KSM-66 Ashwagandha

Ixoreal Biomed Private Ltd, Hyderabad, India

Described as a broad-spectrum phyto-pharmaceutical extract

Standardised to contain 5% withanolides by HPLC.

Other constituents are listed as alkaloids, short and long-chain amino acids (threonine, valine, methionine, isoleucine, lysine, aspartic acid, and arginine), complex carbohydrates including oligosaccharides/fructo-oligosaccharides, vitamin A, calcium and iron.

Dose used in clinical studies: 

• Oligospermia study: 225 mg thrice daily for 12 weeks.[11] = 34 mg withanolides
• Female sexual dysfunction: 300 mg twice daily for 8 weeks[12] = 30 mg withanolides
• Cardio endurance: 300 mg twice daily 12 weeks.[13] = 30 mg withanolides
• Sub-thyroidism:   300 mg twice daily 12 weeks [8] = 30 mg withanolides 

Swiss Natural - Canada (formerly Swiss Herbal)

Extract ratio: 5:1

Standardisation: 1.5 % withanolides

Dose: 300 mg twice daily = 9 mg

Ashwagandha was more efficacious against anxiety than psychotherapy (n = 40) when tested over 8 weeks. No serious adverse events were observed, and the distribution and frequency of mild adverse events was identical in both groups – and therefore most likely not causally related to the treatment.[14]

Practitioner products in Australia containing KSM-66

Bioceuticals - AdrenoPS

KSM-66 Ashwagandha with Relora (magnolia and philodendron)

Withania somnifera (winter cherry) 1.88g equiv. to withanolides  7.5mg

Four tablets correspond to the dose* used in the clinical trials. 

Bioceuticals - Adrenoplex 

Contains 150 mg KSM-66.

Four tablets would provide the equivalent dosage* used in the clinical trials.

Liquid Extracts

MediHerb

Withania 2:1 root extract quantified to contain not-less-than 4.0 mg/mL of withanolides. 8 ml of this extract would provide 32 mg withanolide which is equivalent to the dosage* used in the clinical trials. The weekly dose would be about 55 ml.

Optimal Rx

Withania root, 1.5:1, quantified to contain not-less-than 4.5 mg/mL withanolides.

7 ml of this extract would provide 32 mg withanolide which is equivalent to the dosage* used in the clinical trials. The weekly dose would be about 49 ml.

Retail products in Australia containing KSM-66

Caruso's - Ashwagandha

Each tablet contains: 600 mg Withania somnifera (KSM-66® Ashwagandha) extract equiv. to 7.5 g dried root (7500mg) Standardised to 30 mg withanolides.

One tablet corresponds to the dose* used in the clinical trials. 

Nature’s Way

Each tablet contains: Withania Somnifera (KSM-66) 300mg 

Equivalent to Withania Somnifera Root Dry 3750mg 

Equivalent to withanolides 15mg

Two tablets correspond to the dose* used in the clinical trials.

Health Thru Nutrition- Ashwagandha 

500mg Pure KSM-66 5%

1 tablet is close to the dose* used in the clinical trials.

Equivalent to 25 mg withanolides

Herbs of Gold - Mind Ease 

600 mg KSM-66 per tablet

Equivalent to 30 mg withanolides

Number of tablets: 60

1 tablet is equivalent to the dosage* used in the clinical trials.

There may be others including many KSM-66 containing products from the US on Australian websites.

Summary

• Two studies used the Shoden product which is highly concentrated at 34% withanolides. The other studies were based on extracts containing 5% withanolides (KSM-66, Ixoreal Biomed) or 8% withanolides (Sensoril). 
• KSM-66 is used in Adrenoplex (150 mg, need 4 tablets for clinically effective dosage*) from Bioceuticals and in a range of retail products.
• Sensoril is used in Nature’s Own EQ Control.
• Neither of the two case reports provide evidence of a causal relationship between Withania and the development of thyrotoxicosis. That Withania was shown to normalise thyroid hormone levels in patients with subclinical hypothyroidism in the clinical trial does not mean that Withania can cause thyrotoxicosis or that it is necessarily contraindicated in hyperthyroidism. Nevertheless, we should use Withania with caution in patients with Graves’ disease.
• No reproductive toxicity found in animal studies Sharma 1986 [15]

*Warning. As there are a number of therapeutically active components in Withania somnifera and a lack of transparency over the source to benefit controls between batches and the finished product specifications, a direct extrapolation of “dosage” between products is not reliable but is provided for readers with this warning.

References

1.         Tandon, N. and S.S. Yadav, Safety and clinical effectiveness of Withania Somnifera (Linn.) Dunal root in human ailments. J Ethnopharmacol, 2020. 255: p. 112768.

2.         Lopresti, A.L., P.D. Drummond, and S.J. Smith, A Randomized, Double-Blind, Placebo-Controlled, Crossover Study Examining the Hormonal and Vitality Effects of Ashwagandha ( Withania somnifera) in Aging, Overweight Males. Am J Mens Health, 2019. 13(2): p. 1557988319835985.

3.         Lopresti, A.L., et al., An investigation into the stress-relieving and pharmacological actions of an ashwagandha (Withania somnifera) extract: A randomized, double-blind, placebo-controlled study. Medicine (Baltimore), 2019. 98(37): p. e17186.

4.         Chengappa, K.N., et al., Randomized placebo-controlled adjunctive study of an extract of withania somnifera for cognitive dysfunction in bipolar disorder. J Clin Psychiatry, 2013. 74(11): p. 1076-83.

5.         Chengappa, K.N.R., et al., Adjunctive Use of a Standardized Extract of Withania somnifera (Ashwagandha) to Treat Symptom Exacerbation in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study. J Clin Psychiatry, 2018. 79(5).

6.         Ziegenfuss, T.N., et al., Effects of an Aqueous Extract of Withania somnifera on Strength Training Adaptations and Recovery: The STAR Trial. Nutrients, 2018. 10(11).

7.         Choudhary, D., S. Bhattacharyya, and K. Joshi, Body Weight Management in Adults Under Chronic Stress Through Treatment With Ashwagandha Root Extract: A Double-Blind, Randomized, Placebo-Controlled Trial. J Evid Based Complementary Altern Med, 2017. 22(1): p. 96-106.

8.         Sharma, A.K., I. Basu, and S. Singh, Efficacy and Safety of Ashwagandha Root Extract in Subclinical Hypothyroid Patients: A Double-Blind, Randomized Placebo-Controlled Trial. J Altern Complement Med, 2018. 24(3): p. 243-248.

9.         van der Hooft, C.S., et al., [Thyrotoxicosis following the use of ashwagandha]. Ned Tijdschr Geneeskd, 2005. 149(47): p. 2637-8.

10.       Curry, K.M., et al., Thyrotoxicosis with Ashwagandha: A Case Report. SSRN, 2019.

11.       Ambiye, V.R., et al., Clinical Evaluation of the Spermatogenic Activity of the Root Extract of Ashwagandha (Withania somnifera) in Oligospermic Males: A Pilot Study. Evid Based Complement Alternat Med, 2013. 2013: p. 571420.

12.       Dongre, S., D. Langade, and S. Bhattacharyya, Efficacy and Safety of Ashwagandha (Withania somnifera) Root Extract in Improving Sexual Function in Women: A Pilot Study. Biomed Res Int, 2015. 2015: p. 284154.

13.       Choudhary, B., A. Shetty, and D.G. Langade, Efficacy of Ashwagandha (Withania somnifera [L.] Dunal) in improving cardiorespiratory endurance in healthy athletic adults. Ayu, 2015. 36(1): p. 63-8.

14.       Cooley, K., et al., Naturopathic care for anxiety: a randomized controlled trial ISRCTN78958974. PLoS One, 2009. 4(8): p. e6628.

15.       Sharma, S. and S.M. Dahanukar, Effects of long-term administration of the roots of Aswagandha (Withania somnifera) and Shartavari (Aspararus racemosus) in rats. . Indian Drugs, 1986. 23.